NK cells have the ability to become activated under the appropriate conditions by utilizing one or more cell surface receptors that are capable of inducing NK cell cytokine production and/or cytotoxicity. The expression of a variable array of inhibitory receptors on the surface of NK cells act to counterbalance the positive signals initiated through activating receptors. Increasing evidence suggests an important role for both activating and inhibitory NK cell receptors in an appropriate and controlled NK response to infectious agents. During the previous funding period we found that Killer Cell Lectin Like Receptor G1 (KLRG1), an evolutionary conserved inhibitory receptor expressed at the NK cell surface is a ligand for N-cadherin and E-cadherin molecules. Classical cadherins are Ca2+ dependent homophilic cell adhesion molecules expressed in almost all tissues. Classical cadherins are transmembrane components of a number of cellular junctions. The binding of these immune receptors to cadherin is intriguing and opens new unanticipated avenues of research. Our recent preliminary data demonstrate that the KLRG1/cadherin interaction has an impact not only on NK cells but also on cells expressing E-cadherin such as dendritic cells. We therefore propose to study the consequence of cadherin engagement by KLRG1 at the cellular and molecular levels. In Specific Aim 1, we will investigate the consequence of cadherin/KLRG1 interaction in vitro in order to determine the functions of KLRG1 associated phosphatases. In Specific Aim 2, we will determine how KLRG1 interaction with cadherin influences cadherin stability, cell surface expression, and trafficking. In Specific Aim 3, we propose to regulate the intensity of cadherin/KLRG1 interaction in vivo and to examine the consequences of a decreased or increased interaction during viral infection. We believe the results of these studies will expand our current knowledge of NK cell and dendritic cell biology. It will also provide insights into the function of cadherins during an immune response to pathogens.